Histogenesis and differentiation of the mammalian tooth organ is dependent on sequential, reciprocal epithelial-mesenchymal interactions. Ameloblastomas represents derangements in these interactions. Understanding the molecular pathogenesis for this tumor will provide important insight into normal epithelialmesenchymal organogenetic interactions and will also provide prognostic markers indicative of aggressive behavior. We will test the hypothesis that the molecular pathogenesis for ameloblastomas is seated in the inappropriate expression of the substrate adhesion molecule (1-4 galactosyl transferase, GT) and/or a mitogen (preproepidermal growth factor, ppEGF and/or insulin-like growth factor IGF). Perturbation in the spatial and temporal pattern for expression of these molecules perverts the normal pattern of reciprocal, sequential tissue interactions responsible for morphogenesis and differentiation. We will also test the hypothesis that the absence of an enamel extracellular matrix in ameloblastomas is due to the transcription of both the sense and antisense strands of the amelogenin gene, thus preventing amelogenin protein translation. Lastly, we propose to identify prognostic markers for ameloblastomas. By quantitative determining the level of amelogenin gene expression and/or galactosyl transferase expression and/or growth factor expression as a marker(s) for the degree of differentiation of the tumor which will correlate with its pathologic behavior. The experimental progress by this research group includes the development of high resolution in situ hybridization histochemistry using radiolabeled complementary RNA or oligononucleotide probes and clearly provides evidence for the feasibility of the proposed studies. We will critically examine our hypothesis through the performance of the following specific aims: i) determine the qualitative and quantitative level of expression of amelogenin gene transcription products in ameloblastomas; ii) determine if both strands of the amelogenin gene are transcribed in ameloblastomas; iii) determine the pattern of expression for 1-4 galactosyl transferase in ameloblastomas; iv) determine the pattern of expression of growth factors(s) in ameloblastomas; and v) determine if the level of epithelial differentiation as reflected by specific gene expression correlates with the pathologic behavior of the tumor.
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